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With an Alzheimer’s epidemic looming, scientists, health officials, policymakers, and the public are asking if anything can slow down this disease. Some prevention trials in the U.S. will test drug interventions (see ARF related news story), but what about lifestyle modifications, such as eating better or exercising more? Some data suggest that tweaks in our routine could help, but in 2010 a panel from the National Institutes of Health deemed that evidence insufficient to justify formal recommendations (see ARF related news story). Now, three large, randomized controlled trials in Europe are for the first time testing prospectively whether multifaceted lifestyle changes can prevent dementia in healthy, non-demented people. Key researchers from these initiatives have come together under the European Dementia Prevention Initiative (EDPI), a collaboration established to help them share data and design new studies.

Retrospective analyses of large populations suggest that mental stimulation, diet, exercise, and other healthy behaviors can benefit cognition. “We have quite a lot of epidemiological studies showing that these modifiable risk factors are related to dementia,” said Miia Kivipelto, University of Eastern Finland, Kuopio. “Now we need to move from observation to action, and try to show in a clinical trial that these lifestyle changes really can modify or postpone the cognitive impairments.”

One ongoing trial is PreDIVA (Prevention of Dementia by Intensive Vascular Care). Overseen by Willem van Gool from the University of Amsterdam, the Netherlands, it tests if intense treatment of cardiovascular risk factors, above and beyond standard care, prevents dementia or brain changes as seen by structural magnetic resonance imaging (MRI). For six years, half of the 3,534 healthy participants, aged 70 to 78, receives standard care (though any baseline measurements indicating cardiovascular problems are reported to the patients' general practitioners). The other half sees a nurse every four months to be thoroughly monitored and treated for hypertension and high plasma cholesterol. The nurse advises participants to quit smoking, exercise more, and adopt a healthier lifestyle. Van Gool and colleagues have analyzed the first two years of data, which indicate that blood pressure dropped almost twice as much in the intervention group as in the control group. Whether this will reduce the incidence of dementia or brain atrophy remains to be seen.

Treating vascular risk factors is likely appropriate for staving off late-onset dementia, said Edo Richard, University of Amsterdam, a lead investigator in the PreDIVA study. Many people with sporadic Alzheimer’s suffer from mixed dementias, which may include vascular lesions in the brain. “If we look at data from epidemiological studies, there clearly is a good reason to figure out, in randomized controlled trials, if treatment of these vascular risk factors will prevent cognitive decline,” Richard told Alzforum. In fact, if U.S. trials targeting Aβ and tau pathology in older, plaque-positive people overlook cardiovascular factors, they may run a risk of generating uninterpretable results, cautioned Kenneth Kosik, University of California, Santa Barbara. “We may discard an Alzheimer's treatment because it didn’t show an effect on the component of the dementia due to vascular disease, even though it is efficacious on the AD component,” he told Alzforum.

Vascular factors are specifically targeted in the ongoing FINGER trial (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) as well. Led by Kivipelto, this multicenter Finnish study follows 1,200 people aged 60-77 who are not impaired at enrollment but are at risk for cognitive decline according to the CAIDE Dementia Risk Score, which is based on physiological and demographic parameters (see Kivipelto et al., 2006). For two years, an intervention group will see study dieticians, nurses, and physical therapists several times a year for nutritional counseling, exercise guidance, cognitive training, social activity training, and metabolic and vascular risk management. Participants will keep track of their activities in study diaries. Controls will receive standard healthcare, but not the same intense monitoring and one-on-one advice. Kivipelto said that preliminary results suggest an improved cardiovascular risk profile for the intervention group. Cognitive outcomes of the modified Neuropsychological Test Battery, Stroop, and Trail Making tests will be available in 2014, said Kivipelto, and the researchers will follow up with participants again after five more years. In a subgroup of patients, researchers will also observe changes in cerebrospinal fluid AD biomarkers and structural MRI scans (brain volume), as well as positron emission tomography with Pittsburgh Compound-B (amyloid load) and fluorodeoxyglucose (glucose metabolism). Scans will be taken at the beginning of the study and at both follow-ups.

The EDPI umbrella also covers the Multi-Domain Alzheimer's Prevention Trial (MAPT), an ongoing multicenter study. Led by Bruno Vellas of the University Hospital Center, Toulouse, France, MAPT modifies lifestyle factors in addition to administering omega-3 fatty acid to prevent cognitive decline in people at risk. So far, Vellas and colleagues have recruited more than 1,600 people, aged 70 or older. All complain of memory problems, walk with a slow gait, or have lost the ability to perform one everyday task, such as balancing a checkbook. Over the course of three years, four treatment groups each receive an omega-3 fatty acid supplement, a multi-domain intervention, both, or neither. The multi-domain intervention involves weekly or monthly counseling and in-session activities with nutritional, exercise, cognitive, and social experts. Like the FINGER trial, participants document their adherence to the regimen in diaries.

In 2014, the researchers will analyze changes on the Grüber and Buschke test, administered at six, 12, 24, and 36 months. Participants will receive one last follow-up at five years, as part of the MAPT PLUS extension trial. Though no preliminary data are yet available for MAPT, Sandrine Andrieu of INSERM at University of Toulouse found that the education level of the sample population exceeded that of the general population. A higher level of cognitive reserve could affect cognitive decline over time and make it difficult to extrapolate findings to the general population, Andrieu told Alzforum. Scientists question whether other population-based studies, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), may face the same dilemma.

For his part, Richard saw enough commonalities among these three studies to bring them together to form the EDPI, which launched in April of 2011. All three involve multi-domain lifestyle changes in elderly, non-demented people. EDPI aims to facilitate data sharing and practical support among the studies. One goal is to learn how best to design prevention trials. As such, EDPI resembles to the Collaboration for Alzheimer’s Prevention (CAP), which brings together three separate but complementary prevention trials in the U.S. (ARF related news story). CAP incorporates trials that will examine amyloid-modifying treatments, in cognitively normal younger people from families carrying familial AD (the combined API/DIAN trial), older people who have some genetic risk for AD (an API trial), or older individuals who have evidence of plaque deposition in the brain (the A4 trial).

Not only do the two umbrella initiatives take different tacks to intervention, but they may actually target two different diseases, believes Richard (see Richard et al., 2012, and van Gool and Eikelenboom, 2000). EDPI is probably capturing mixed pathologies with a strong vascular component in older people, whereas CAP focuses on earlier-onset AD or Aβ as the original physiological mechanism. Their respective groups are not exclusive to Europe or the U.S., however. Many EDPI-like studies are being done in the U.S., though most target one intervention, as in the systolic blood pressure intervention (SPRINT) trial, for example. Likewise, CAP studies span different countries.

One EDPI goal is to pool data where possible in order to expand the number of study participants. “The power of combined studies is that the larger the sample, the stronger the inferences that can be made,” said John Morris, Washington University, St. Louis, Missouri, a CAP member and principal investigator on the DIAN consortium. In addition, the EDPI scientists plan to learn from each other’s studies by comparing recruitment strategies, inclusion criteria, adherence and dropout, and the intensity of interventions to determine how best to design future multinational intervention trials for dementia prevention (see Richard et al., 2012). EDPI recently learned that it would receive a grant from the European Commission’s Seventh Framework Programme to design and carry out the five-year Healthy Aging Through Internet Counseling of the Elderly (HATICE) study. Though still in the design phase, the study will enroll 4,600 community-dwelling participants in the Netherlands, Finland, and France who are older than 65 and at risk for cardiovascular disease. The aim is to see if a combination of online and nurse support prevents cardiovascular disease and dementia. The study design will draw from insights the group gained comparing its three current studies.

Will any of the interventions used in the current studies benefit cognition? The researchers acknowledge that they may not. Would that mean vascular and lifestyle factors are negligible in preventing dementia? Absolutely not, the same researchers agree. An effect could be lost due to a number of factors, including use of the wrong assessment tool, premature follow-up, inadequate compliance, or starting the intervention too late.

The last one in particular is a distinct possibility, said Deborah Blacker, Massachusetts General Hospital, Charlestown. “One of the big controversies is whether late-life risk factors or midlife factors make a difference,” she said. Some cardiovascular and health changes may protect younger, but not older people from dementia. The trouble is, it would take decades to assess a midlife intervention with late-life follow-up in an RCT, she told Alzforum. This is a tough issue for the dementia field (see AlzRisk related discussion). Since AD is now understood to begin at least a decade before symptoms appear, the earliest prevention trials may be practically and financially prohibitive. “Clinical trials are the gold standard in a variety of ways, but they have limitations [for dementia] because of this timing issue,” said Blacker.

Nevertheless, wide-ranging prevention studies are starting to run the gamut of disease forms from young onset to old, and of potential preventative measures from drugs to lifestyle changes. “We need a broad range of studies both looking at [the effect of] lifestyle and drug interventions on prevention of cognitive decline and dementia,” said Laurie Ryan, National Institute on Aging, Bethesda, Maryland. “It’s good that we’re looking at a host of things, not just one,” she told Alzforum.

In future, collaboration between the two major umbrella groups could shed even more light on treatment options, suggested Deborah Barnes, University of California, San Francisco. “It would be great if EDPI and CAP could work together to harmonize some of their outcome measures, so that the effects of behavioral and pharmacologic approaches could be directly compared,” she told Alzforum in an e-mail. “It would also be interesting to see whether an intervention that combines behavioral and pharmacologic approaches is more effective than either approach alone.”

EDPI and CAP are not in direct contact yet, Richard told Alzforum in an e-mail. "In the future I think collaboration, where possible, could offer new opportunities and could potentially be of benefit to the field. In spite of the different types of studies and different target populations, several methodological issues in trial design are applicable to all randomized controlled trials that assess cognitive decline or incident dementia."—Gwyneth Dickey Zakaib.